The use of attenuated bacteria that are unable to cause disease triggers a self-limited infection that leads to the stimulation of protective immunity. Attenuated Salmonella vaccines induce cellular immune responses by limited replication in the host, which mimics natural infection and results in strong and long-lasting immunity. Oral vaccination with attenuated Salmonella induces mucosal immunity and prevents infection at the portal of entry for mucosal pathogens.
Avirulent strains of Salmonella can be genetically engineered to stably express, at high levels, colonization and virulence antigens from other bacterial, viral, parasitic, and fungal pathogens. When used for oral immunization, these live avirulent recombinant vaccine strains attach to, invade, and colonize the gut associated lymphoid tissue (GALT) and then pass to other lymphoid tissues, such as mesenteric lymph nodes, liver and spleen. In these lymphoid tissues, the live avirulent recombinant vaccine strains continue to synthesize the foreign colonization or virulence antigens. Since delivery of antigens to the gut associated lymphoid tissue stimulates a generalized secretory immune response, oral immunization with these vaccines stimulates mucosal immunity throughout the body. In addition, systemic and cellular immune responses are elicited against the foreign expressed antigens as well as against Salmonella antigens.
Achieving maximal immune responses to the foreign antigen is dependent upon the amount of the foreign antigen produced by the recombinant avirulent Salmonella and also upon the inherent immunogenic properties of the foreign antigen. Although data to indicate the importance or non importance of antigen location in recombinant avirulent Salmonella is by and large lacking, there are some reasons to believe that the time of onset, magnitude and/or duration, as well as the type of immune response might be influenced by antigen localization in the recombinant avirulent Salmonella vaccine.
S. pneumoniae is the world's foremost bacterial pathogen, causing high morbidity and mortality, even in regions where antibiotics are readily available. It is the single most common cause of community-acquired pneumonia, and has become the most common cause of meningitis in many regions. The pneumococcus is conservatively estimated to kill 1-2 million children under the age of 5 years each year in developing countries, accounting for 20-25% of all deaths in this age group. The problem of pneumococcal disease is being further exacerbated by the rate at which this organism is acquiring drug resistance and the rapid global spread of highly resistant clones. In developed countries this necessitates use of newer, more expensive antimicrobials, but this option is not available in the developing world. Antibodies to pneumococcal capsular polysaccharides can protect against fatal infection and capsule-based human vaccines have been developed. These vaccines provide serotype-specific protection, and the adult formulation contains a mixture of the 23 most common polysaccharides. However, there are over 90 distinct capsular serotypes of S. pneumoniae, and geographic differences in serotype prevalence have resulted in suboptimal protection in many countries. Moreover, this vaccine is not immunogenic in children under two years old who have the highest disease burden. A more immunogenic 7-valent protein-polysaccharide conjugate vaccine has recently been licensed for children that is quite effective against invasive disease and provides some protection against nasal carriage and otitis media. Unfortunately, it covers only 50-60% of pneumococcal infections in many developing countries. Alarmingly, trials of the conjugate vaccine have shown that although carriage of vaccine types was reduced, the vacated niche was promptly occupied by non-vaccine serotypes known to cause invasive disease. This “replacement carriage” has translated into a significant increase in cases of disease caused by non-vaccine serotypes in conjugate vaccine recipients. The remedy for this problem has been to add more capsular types to the conjugate vaccine. However, at its current cost of US$260/course the 7-valent vaccine is already too expensive for use in the developing countries. Thus, continued use of vaccines that simply alter the serotype distribution of pneumococcal disease are likely to have little long-term impact on pneumococcal disease, especially in the poorest countries where most of the disease occurs.
Consequently, there is a need in the art for an effective vaccine against Streptococcus pneumoniae. 